We are interested in developing strategies for the reconstitution of the dopaminergic (DA) nigrostriatal (NS) pathway that degenerates in Parkinson's disease, an important goal because of the inadequacy of current long-term treatments. Attempts to reconstruct this pathway through transplantation of precursor cells or neurons into the nigra of the adult fail, likely as a result of 1) the presence of inhibitory molecules and/or 2) the absence of trophic and guidance molecules in the adult CNS. Here we propose that an understanding of the molecular events that regulate the development of the nigrostriatal pathway will provide insights for strategies designed to improve NS pathway regeneration in the adult milieu. We propose - and have exciting preliminary data to support - that axon guidance molecules (AGMs), important molecules that direct the development of other projection pathways in the CNS, are expressed in the developing DA NS pathway. A series of experiments are proposed to elucidate the role played by AGMs and their receptors in the development of the NS pathway. Our specific aims are to: 1) Define those AGMs whose receptors are expressed in the developing axons of nigral DA neurons;2) Define the expression of AGM ligands in relation to the developing NS pathway;3) For those AGMs that are expressed in an appropriate anatomical relationship to influence NS development, and whose receptors are expressed in developing DA neurons, directly demonstrate chemotropic effects on fetal nigral DA neurons in vitro, and their importance in the development of the NS pathway with blocking studies ex vivo. The outcome of the experiments outlined in this proposal will hopefully be the refinement of means to counteract the inhibitory milieu of the adult injured nervous system, and recapitulate the attractive and repulsive factors that direct axonal outgrowth during development, thereby paving the way for novel reconstructive and regenerative strategies to ameliorate the symptoms of Parkinson's disease. The insights derived from these studies may also have applicability in other neurodegenerative diseases, brain injury and stroke. The research outlined is part of a customized five-year plan of training and career development for the Principal Investigator. The proposal includes active mentoring by experienced scientists, access to diverse resources, and an environment uniquely suited to help the PI develop as an independent neurosurgeon-neuroscientist.